This invention relates to a method for the preparation of imidazolutidine, a key intermediate in the synthesis of a series of Angiotensin II receptor antagonists. Representative of these antagonists are: ##STR2## which are disclosed and claimed in U.S. application Ser. No. 516,286 filed May 4, 1990 now U.S. Pat. No. 5,332,744.
The methodology utilized for the synthesis of the imidazopyridine heterocycle relies upon the preparation of a 2,3-diamino precursor using classical chemistry, followed by condensation of the diamine with the appropriate carboxylic acid to form the imidazole. These approaches are often inefficient and lack regio-control. ##STR3##
One of the approaches utilized is described in the above scheme, which is dependent upon obtaining a supply of 2-amino-4,6-lutidine, a starting material, which is available in an impure form. The synthetic route requires a three-step sequence to generate 2,3-diamino-4,6-lutidine, 4. The first of these steps is the bromination of 2-amino-4,6-lutidine with N-bromosuccimide (NBS) added as either a solution in acetone or as a solid to produce 2-amino-5-bromo-4,6-lutidine. Depending upon the addition method used the amounts of the two by-products varied, the 3-bromo analog and the 3,5-dibromo analog. See Table 1 below.
TABLE 1 ______________________________________ Method 3-Bromo analog 3.5-Dibromo analog ______________________________________ solution 7% 1% solid 4.8 % 8.4% ______________________________________
The second step is the nitration of the 2-amino-5-bromo-4,6-lutidine to produce the 2-amino-5-bromo-3-nitro-4,6-lutidine. This nitration requires the overnight reaction of the 5-bromo analog with nitric acid and sulfuric acid as a solvent. Over nitration of the 2-amino-5-bromo-4,6-lutidine compound produces a shock-sensitive pyridone compound: ##STR4## The final step in preparing the diamine is the hydrogenation of the nitro group using palladium on carbon as a catalyst.
The 2,3-diamino-4,6-lutidine is then condensed with propionic acid to form the imidazole ring. This condensation requires large quantities of propionic acid due to the necessity of a constant feed of propionic acid into the reaction.
The process of the instant invention solves the problems associated with using the current methodologies to produce large quantities of the compounds of formula I. The problems include expensive starting materials and use of toxic catalysts and reagents.